Nalorphine: increased sensitivity of monkeys formerly dependent on morphine.

Three rhesus monkeys Macaca mulatta, formerly dependent on morphine, had increased sensitivity to nalorphine's effect of suppressing operant responding for food, as compared with two monkeys with no history of morphine exposure. Within the dose range employed, nalorphine injections produced emesis, salivation, and hyperirritability in formerly morphine-dependent monkeys but not in controls.

Effects of pethidine and nalorphine on the mechanical and electrical activities of mammalian isolated ventricular muscle.

1. The strength of the isometric mechanical contraction of electricallydriven ventricular muscle has been recorded simultaneously with the resting and action potentials; the effects of pethidine and of nalorphine on these parameters have been studied.2. When lower concentrations of pethidine (0.22-6.5 mug/ml) were perfused, isometric peak tension was decreased in parallel with the maximum upstroke velocity of the action potential; these actions are considered to result from membrane stabilization. At higher concentrations (11.8-109 mug/ml) pethidine usually produced, in addition, a progressive decrease in the resting and action potentials associated with marked irregularities in, or even abolition of, the mechanical response. It is suggested that these effects of the higher doses might be due to a depression of ATPase activity in the myocardial membrane.3. Compared with pethidine, nalorphine had similar, but weaker, actions.

Differential cross-tolerance between analgesia produced by alpha 2-adrenoceptor agonists and receptor subtype selective opioid treatments.

Analgesic cross-tolerance between alpha 2-adrenoceptor and opioid receptor agonists was studied using the mouse tail-flick assay. Mice tolerant to clonidine (0.3 mg/kg s.c.) or xylazine (7 mg/kg s.c.) were cross-tolerant to morphine (5 mg/kg s.c.), nalorphine (70 mg/kg s.c.) and supraspinal [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO; 4 ng i.c.v.), but not trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl] benzeneacetamide methanesulfonate (U50,488; 5 mg/kg s.c.), spinal DAMGO (10 ng i.t.), supraspinal [D-Pen2,D-Pen5]enkephalin (DPDPE; 9 micrograms i.c.v.) or spinal DPDPE (700 ng i.t.). In the complimentary studies, mice tolerant to morphine and nalorphine were cross-tolerant to both of the alpha 2-adrenoceptor agonists, but U50,488 tolerant mice were not. The results suggest differential interactions between alpha 2-adrenoceptor and mu 1-, mu 2-, delta-, kappa 1- and kappa 3-opioid analgesic circuitry.

Possible effects of normetabolites on the subjective and reinforcing characteristics of opioids in animals and man.

When an opioid capable of forming active metabolites is administered, the total pharmacology is the result of interactions of the opioid and such metabolites, especially normetabolites. Normetabolites may affect the morphine-like characteristics of certain opioids and thus influence their reinforcement in animals and man. Most opioids, when administered in single doses, are positively reinforcing in addicts. Oral administration, as compared with parenteral, facilitates the formation of normetabolites. When chronically administered, many opioids, including acetylmethadol, meperidine, morphine, codeine, propoxyphene, and levorphanol, show evidence of a longer half-life for their normetabolites. Normetabolites may have aversive characteristics and thus impair positive reinforcement of the parent drug in animals and man. For example, addicts do not like chronic oral morphine or chronic oral codeine. Conversely, methadone, the normetabolites of which are inactive, is well accepted during chronic oral administration. Drugs which inhibit N-demethylation will increase the agonist potency of opioids having inactive normetabolites (e.g., methadone) but will decrease the agonist potency of opioids having more potent normetabolites than the parent (e.g., acetylmethadol). The divergent responses of addicts to single doses of opiates as compared with chronic doses indicate that chronic addiction tests in man are needed befored relative abuse liability can be predicted.

Taste aversion involving central opioid antagonism is potentiated in morphine-dependent rats.

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.

Nalorphine's ability to substitute for morphine in a drug discrimination procedure is a function of training dose.

Rats trained to discriminate the mu agonists fentanyl or morphine from their respective vehicles generalize to the partial mu agonist nalorphine incompletely and inconsistently. Any number of factors may influence the generalization patterns obtained, one of which being the specific dose of the full opioid agonist used during training, a factor reported to influence generalization with other partial opioid agonists. To assess if training dose influences stimulus generalization to nalorphine and to support its role in the aforementioned variability across studies, in the present experiments rats were trained to discriminate either a low (5.6 mg/kg) or a high (10 mg/kg) dose of morphine from distilled water within the taste aversion baseline of drug discrimination learning. Subjects were then given a range of doses of morphine, nalorphine, methadone, or naloxone to assess the degree of substitution (if any) of these compounds for the training dose of morphine. For all subjects, morphine fully substituted for itself, and the opioid antagonist naloxone failed to substitute for the morphine cue. Rats generalized the morphine cue to nalorphine in subjects trained at the lower dose but not in subjects trained at the higher dose. Rats generalized the morphine cue to methadone in the latter group (the high dose group), indicating that the failure to generalize to nalorphine in this group was not a general inability of an opioid agonist to substitute for morphine. Naloxone blocked morphine stimulus control in all subjects and nalorphine control in the low-dose group for which nalorphine substituted for morphine, suggesting that morphine control (and the nalorphine substitution) was based on opioid activity. These results indicate that the substitution patterns of nalorphine in morphine-trained subjects are a function in part of the dose of morphine used in training and support the position that nalorphine is a partial opioid agonist with intermediate efficacy.

Conditioned nalorphine-induced abstinence changes: persistence in post morphine-dependent monkeys.

Every tenth lever-press of three morphine-dependent rhesus monkeys was reinforced with food. A red light, initially a neutral stimulus, was presented every third or fourth session for 5 min before and 5 min after an intravenous injection of nalorphine, a morphine antagonist that produces an immediate abstinence syndrome in morphine-dependent monkeys. After several pairings, conditioned suppression of lever pressing, heart-rate decrease, vomiting, and excessive salivation were observed during the red-light period before nalorphine injection. No conditioned electrocardiogram, respiration or temperature changes occurred. After 10 red light-nalorphine pairings, morphine administration was completely discontinued and monkeys were then tested monthly for persistence of the conditioned responses. The red light paired with saline injection continued to suppress lever pressing and to produce heart-rate decreases after 60 to 120 days of complete abstinence from morphine. Subsequently, daily presentations of the red light-saline injection complex rapidly extinguished these conditioned responses. Nevertheless, they could be rapidly reinstated by additional nalorphine injections.

Use of droperidol and fentanyl for analgesia and sedation in primates.

A combination of droperidol and fentanyl produces qualitatively similar pharmacologic effects in dogs and primates. Unlike the dog, however, primates did not appear to respond to auditory stimuli. As a result of the analgesic and sedative or tranquil state produced in primates, the animals were easily handled and tolerant of painful stimuli. The principal desirable features of the combination were high analgesic and sedative potency and a rapid onset of action following intramuscular administration. High doses produced respiratory depression. However, this effect was easily reversed by administering nalorphine hydrochloride.

[The mechanism of the action of opiate receptor antagonists in acute shock-induced blood loss]. / K mekhanizmu deistviia antagonistov opiatnykh retseptorov pri ostroi shokogennoi krovopotere.

Experiments on 81 rabbits showed that intravenous infusion of naloxone and nalorphine in different periods of hemorrhagic shock promoted the death of animals. It is concluded that in hypoxia only the antagonistic activity of the drugs is manifested as total inactivation of the endogenous opioid system depriving it of its protective functions. Nalorphine infused after blood reinfusion exhibits agonistic activity and additional activation of the endogenous opioid system promotes the use of the biological reserves by the organism, which saves some of the animals from death or essentially prolongs the survival of the others. Infusion of naloxone after blood transfusion has no effect on the outcome.